OBJECTIVE AND BACKGROUND: Pulmonary fibrosis in sarcoidosis is a significant cause of morbidity and mortality. Various factors have been intensely studied to define the pathogenesis of lung fibrosis in sarcoidosis. Endothelin (ET) consists of three isoforms and is known for its potent vasoconstrictor properties. ET plays an important role in the fibroproliferative process of interstitial lung diseases. METHODS: To investigate the role of ET in the progression of pulmonary fibrosis in sarcoidosis, ET-1 and ET-3 concentrations were measured in BAL fluid (BALF) in 22 non-smoking patients with sarcoidosis and in control subjects (n = 12). Immunoreactivity of ET-1 was also evaluated in alveolar macrophages (AMs) from sarcoidosis patients. To assess the effects of ET in BALF on fibroblast proliferation, human foetal lung fibroblasts were cultured with sarcoidosis or control BALFs in the presence or absence of the ET-receptor antagonist TAK-044. RESULTS: ET-1 levels in sarcoidosis BALF were significantly higher than those in control, whereas ET-3 levels were not different between sarcoidosis and control. ET-1 levels were correlated with the number of AMs in BALF. ET-1-immunoreactivity was found mainly in AM of sarcoidosis BALF. Sarcoidosis BALF significantly stimulated fibroblast proliferation, compared with control BALF, and the fibroblast proliferation induced by sarcoidosis BALF was inhibited by TAK-044. CONCLUSIONS: Increased levels of ET-1 in AM could enhance fibrogenesis in pulmonary sarcoidosis.
OBJECTIVE AND BACKGROUND:Pulmonary fibrosis in sarcoidosis is a significant cause of morbidity and mortality. Various factors have been intensely studied to define the pathogenesis of lung fibrosis in sarcoidosis. Endothelin (ET) consists of three isoforms and is known for its potent vasoconstrictor properties. ET plays an important role in the fibroproliferative process of interstitial lung diseases. METHODS: To investigate the role of ET in the progression of pulmonary fibrosis in sarcoidosis, ET-1 and ET-3 concentrations were measured in BAL fluid (BALF) in 22 non-smoking patients with sarcoidosis and in control subjects (n = 12). Immunoreactivity of ET-1 was also evaluated in alveolar macrophages (AMs) from sarcoidosispatients. To assess the effects of ET in BALF on fibroblast proliferation, human foetal lung fibroblasts were cultured with sarcoidosis or control BALFs in the presence or absence of the ET-receptor antagonist TAK-044. RESULTS:ET-1 levels in sarcoidosis BALF were significantly higher than those in control, whereas ET-3 levels were not different between sarcoidosis and control. ET-1 levels were correlated with the number of AMs in BALF. ET-1-immunoreactivity was found mainly in AM of sarcoidosis BALF. Sarcoidosis BALF significantly stimulated fibroblast proliferation, compared with control BALF, and the fibroblast proliferation induced by sarcoidosis BALF was inhibited by TAK-044. CONCLUSIONS: Increased levels of ET-1 in AM could enhance fibrogenesis in pulmonary sarcoidosis.
Authors: Harry Karmouty-Quintana; Hongyan Zhong; Luis Acero; Tingting Weng; Ernestina Melicoff; James D West; Anna Hemnes; Almut Grenz; Holger K Eltzschig; Timothy S Blackwell; Yang Xia; Richard A Johnston; Dewan Zeng; Luiz Belardinelli; Michael R Blackburn Journal: FASEB J Date: 2012-03-13 Impact factor: 5.191